The shortage of approaches to modify the course of knee osteoarthritis by delaying either disease progression or disability is due in large part to a critical barrier: factors that bear major responsibility for these outcomes and that might become targets for novel therapy are not well understood. In this application, we propose to apply quantitative gait analysis, to evaluate the role of key forces and joint motion measured during ambulation, and state-of-the-art measures of cartilage loss, function, disability, and stage of pain outcomes, to complete these Aims: 1) evaluate the relationship between the external knee adduction angular impulse during the stance phase of gait and subsequent cartilage loss over 4 years; 2) evaluate the relationship between dynamic sagittal plane (flexion-extension) knee motion during gait and subsequent worsening of physical function and disability over 4 years; 3) evaluate the frequency of pain stage progression over 4 years and explore if it is associated with concurrent function decline and disability progression. The study we propose leverages our ongoing cohort study. Baseline and 2-year evaluations of 250 persons with knee OA are funded by the current MCRC and 2 R01s (examining hip muscle strength as well as dynamic instability using quantitative gait analysis). We now propose to add a 4-year evaluation - including MRI acquisition, cartilage thickness and denuded bone area quantification, and function and disability outcome assessment at 4 years - and to derive the gait variables needed for Aims 1 and 2 by computational processing and analysis of baseline and 2-year gait data. The aims we now propose are unique and could not be completed within the ongoing study's scope of work. Without this leveraging, the study we now propose could not be accomplished in one 5-year period. The components of the proposed study will uniquely position us to identify intervention and prevention targets: the longitudinal design and meaningful duration; strategic assessment, using quantitative gait analysis, of key mechanical factors under the dynamic conditions of the most common human weightbearing activity, coupled with direct, state-of-the-art measurement of cartilage loss (Aim 1); and dynamic assessment of critical elements of knee-level joint function coupled with person-level function and disability outcomes (Aim 2). These findings will inform the knee OA natural history paradigm as well as identify as yet untapped targets for novel strategies to prevent cartilage loss, function decline, and disability progression.